Evidence for a Continuum of Genetic, Phenotypic, and Biochemical Abnormalities in Children with Growth Hormone Insensitivity

GH insensitivity (GHI) presents in childhood as growth failure and in its severe form is associated with dysmorphic and metabolic abnormalities. GHI may be caused by genetic defects in the GH-IGF-I axis or by acquired states such as chronic illness. This article discusses the former category. The field of GHI due to mutations affecting GH action has evolved considerably since the original description of the extreme phenotype related to homozygous GH receptor (GHR) mutations over 40 yr ago. A continuum of genetic, phenotypic, and biochemical abnormalities can be defined associated with clinically relevant defects in linear growth. The role and mechanisms of the GH-IGF-I axis in normal human growth is discussed, followed by descriptions of mutations in GHR, STAT5B, PTPN11, IGF1, IGFALS, IGF1R, and GH1 defects causing bioinactive GH or anti-GH antibodies. These defects are associated with a range of genetic, clinical, and hormonal characteristics. Genetic abnormalities causing growth failure that is less severe than the extreme phenotype are emphasized, together with an analysis of height and serum IGF-I across the spectrum of different types of GHR defects. An overall view of genotype and phenotype relationships is presented, together with an updated approach to the assessment of the patient with GHI, focusing on investigation of the GH-IGF-I axis and relevant molecular studies contributing to this diagnosis. (Endocrine Reviews 32: 472-497, 2011) I. Introduction II. The GH-IGF-I Axis in Human Growth A. Physiology of GH and the IGF-I system in relation to linear growth B. Mechanisms of GH and IGF-I actions C. Effects of human GH-IGF-I axis mutations on linear growth III. Molecular Defects Causing GH Insensitivity A. The GH receptor (GHR) B. GHR mutations associated with a range of phenotypes C. STAT5B mutations D. Mutations of SHP-2 (encoded by PTPN11) E. IGF1 mutations F. IGFALS mutations G. IGFIR mutations H. GH1 mutations causing biologically inactive GH I. GHI deletions (type IA GH deficiency) with anti-GH antibodies IV. The Continuum of Phenotypic Features A. GHR mutations B. STAT5B and IGFALS mutations C. IGF1 and IGF1R mutations V. The Continuum of Biochemical Changes A. GHR mutations B. STAT5B and IGFALS mutations C. IGF1 and IGF1R mutations VI. An Updated Approach to the Investigation of GH Insensitivity A. Investigations of the GH-IGF-I axis B. The IGF-I generation test C. Genetic investigations VII. Conclusions and Future Perspectives